Yumi Takasaki, Masako Iwanaga, Yoshitaka Imaizumi, Masayuki Tawara, Tatsuro Joh, Tomoko Kohno, Yasuaki Yamada, Shimeru Kamihira, Schuichi Ikeda, Yasushi Miyazaki, Masao Tomonaga, Kunihiro Tsukasaki
Long-term study of indolent adult T-cell leukemia-lymphoma.
Blood. 2010 Jun 3;115(22):4337-43. doi: 10.1182/blood-2009-09-242347. Epub 2010 Mar 26.
Abstract/Text
The long-term prognosis of indolent adult T-cell leukemia-lymphoma (ATL) is not clearly elucidated. From 1974 to 2003, newly diagnosed indolent ATL in 90 patients (65 chronic type and 25 smoldering type) was analyzed. The median survival time was 4.1 years; 12 patients remained alive for more than 10 years, 44 progressed to acute ATL, and 63 patients died. The estimated 5-, 10-, and 15-year survival rates were 47.2%, 25.4%, and 14.1%, respectively, with no plateau in the survival curve. Although most patients were treated with watchful waiting, 12 patients were treated with chemotherapy. Kaplan-Meier analyses showed that advanced performance status (PS), neutrophilia, high concentration of lactate dehydrogenase, more than 3 extranodal lesions, more than 4 total involved lesions, and receiving chemotherapy were unfavorable prognostic factors for survival. Multivariate Cox analysis showed that advanced PS was a borderline significant independent factor in poor survival (hazard ratio, 2.1, 95% confidence interval, 1.0-4.6; P = .06), but it was not a factor when analysis was limited to patients who had not received chemotherapy. The prognosis of indolent ATL in this study was poorer than expected. These findings suggest that even patients with indolent ATL should be carefully observed in clinical practice. Further studies are required to develop treatments for indolent ATL.
Y Yamada, M Tomonaga, H Fukuda, S Hanada, A Utsunomiya, M Tara, M Sano, S Ikeda, K Takatsuki, M Kozuru, K Araki, F Kawano, M Niimi, K Tobinai, T Hotta, M Shimoyama
A new G-CSF-supported combination chemotherapy, LSG15, for adult T-cell leukaemia-lymphoma: Japan Clinical Oncology Group Study 9303.
Br J Haematol. 2001 May;113(2):375-82.
Abstract/Text
This phase II trial was performed to evaluate the efficacy of a new granulocyte colony-stimulating factor (G-CSF)-supported multi-agent chemotherapy protocol, LSG15, for aggressive adult T-cell leukaemia-lymphoma (ATL). Ninety-six previously untreated patients with aggressive ATL were enrolled and grouped as: acute type (58), lymphoma type (28) and unfavourable chronic type (10). Therapy consisted of seven cycles of VCAP (vincristine, cyclophosphamide, doxorubicin and prednisone), AMP (doxorubicin, ranimustine and prednisone) and VECP (vindesine, etoposide, carboplatin and prednisone). G-CSF was administered during the intervals between chemotherapy until neutrophil reconstitution was achieved. Eighty-one per cent of the 93 eligible patients responded [95% confidence interval (CI), 71.1-88.1%], with 33 patients obtaining complete response (35.5%) and 42 obtaining partial response (45.2%). The median survival time (MST) after registration was 13 months and the median follow-up duration of the 20 surviving patients was 4.2 years (range 2.8-5.6). Overall survival at 2 years was estimated to be 31.3% (95% CI, 22.0-40.5%). Grade 4 haematological toxicity of neutropenia and thrombocytopenia were observed in 65.3% and 52.6% of the patients respectively, but grade 4 non-haematological toxicity was observed in only one patient. LSG15 is feasible with mild non-haematological toxicity and improved the clinical outcome of ATL patients. MST and overall survival at 2 years were superior to those obtained by our previous trials.
Kunihiro Tsukasaki, Atae Utsunomiya, Haruhiko Fukuda, Taro Shibata, Takuya Fukushima, Yoshifusa Takatsuka, Shuichi Ikeda, Masato Masuda, Haruhisa Nagoshi, Ryuzo Ueda, Kazuo Tamura, Masayuki Sano, Saburo Momita, Kazunari Yamaguchi, Fumio Kawano, Shuichi Hanada, Kensei Tobinai, Masanori Shimoyama, Tomomitsu Hotta, Masao Tomonaga, Japan Clinical Oncology Group Study JCOG9801
VCAP-AMP-VECP compared with biweekly CHOP for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study JCOG9801.
J Clin Oncol. 2007 Dec 1;25(34):5458-64. doi: 10.1200/JCO.2007.11.9958. Epub 2007 Oct 29.
Abstract/Text
PURPOSE: Our previous phase II trial for treating human T-lymphotropic virus type I-associated adult T-cell leukemia-lymphoma (ATLL) with vincristine, cyclophosphamide, doxorubicin, and prednisone (VCAP), doxorubicin, ranimustine, and prednisone (AMP), and vindesine, etoposide, carboplatin, and prednisone (VECP) showed promising results. To test the superiority of VCAP-AMP-VECP over biweekly cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), we conducted a randomized controlled trial exclusively for ATLL.
PATIENTS AND METHODS: Previously untreated patients with aggressive ATLL were assigned to receive either six courses of VCAP-AMP-VECP every 4 weeks or eight courses of biweekly CHOP. Both treatments were supported with granulocyte colony-stimulating factor and intrathecal prophylaxis.
RESULTS: A total of 118 patients were enrolled. The complete response (CR) rate was higher in the VCAP-AMP-VECP arm than in biweekly CHOP arm (40% v 25%, respectively; P = .020). Progression-free survival rate at 1 year was 28% in the VCAP-AMP-VECP arm compared with 16% in the CHOP arm (P = .100, two-sided P = .200). Overall survival (OS) at 3 years was 24% in the VCAP-AMP-VECP arm and 13% in the CHOP arm (P = .085, two-sided P = .169). For VCAP-AMP-VECP versus biweekly CHOP, grade 4 neutropenia, grade 4 thrombocytopenia, and grade 3 or 4 infection rates were 98% v 83%, 74% v 17%, and 32% v 15%, respectively. There were three toxic deaths in the VCAP-AMP-VECP arm.
CONCLUSION: The longer OS at 3 years and higher CR rate with VCAP-AMP-VECP compared with biweekly CHOP suggest that VCAP-AMP-VECP might be a more effective regimen at the expense of higher toxicities, providing the basis for future investigations in the treatment of ATLL.
T Fukushima, Y Miyazaki, S Honda, F Kawano, Y Moriuchi, M Masuda, R Tanosaki, A Utsunomiya, N Uike, S Yoshida, J Okamura, M Tomonaga
Allogeneic hematopoietic stem cell transplantation provides sustained long-term survival for patients with adult T-cell leukemia/lymphoma.
Leukemia. 2005 May;19(5):829-34. doi: 10.1038/sj.leu.2403682.
Abstract/Text
Adult T-cell leukemia/lymphoma (ATLL) is a distinct peripheral T-cell neoplasm that is highly resistant to chemotherapy. Several groups, including ours, have reported encouraging results of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with ATLL. To confirm our previous report and to establish the basis for a phase II clinical study, we analyzed 40 allo-HSCT for acute and lymphoma types of ATLL in seven institutions in Japan between 1997 and 2002. All evaluable cases entered complete remission (CR) after allo-HSCT and the median survival time was 9.6 months for all patients. The estimated 3-year overall and relapse-free survival, and disease relapse were 45.3, 33.8 and 39.3%, respectively. Among 10 cases with ATLL relapse, five cases achieved CR again: three by the reduction or cessation of immunosuppressive agents, which suggested a graft-versus-ATLL (GvATLL) effect. However, univariate or multivariate analysis did not show any benefit of graft-versus-host disease (GVHD) on the prevention of relapse. These results suggested that allo-HSCT was effective for some patients with aggressive ATLL, and that the GvATLL effect could be achieved even without GVHD. A new phase II trial to test the efficacy of allo-HSCT for ATLL is warranted.
Masakatsu Hishizawa, Junya Kanda, Atae Utsunomiya, Shuichi Taniguchi, Tetsuya Eto, Yukiyoshi Moriuchi, Ryuji Tanosaki, Fumio Kawano, Yasushi Miyazaki, Masato Masuda, Koji Nagafuji, Masamichi Hara, Minoko Takanashi, Shunro Kai, Yoshiko Atsuta, Ritsuro Suzuki, Takakazu Kawase, Keitaro Matsuo, Tokiko Nagamura-Inoue, Shunichi Kato, Hisashi Sakamaki, Yasuo Morishima, Jun Okamura, Tatsuo Ichinohe, Takashi Uchiyama
Transplantation of allogeneic hematopoietic stem cells for adult T-cell leukemia: a nationwide retrospective study.
Blood. 2010 Aug 26;116(8):1369-76. doi: 10.1182/blood-2009-10-247510. Epub 2010 May 17.
Abstract/Text
Allogeneic hematopoietic stem cell transplantation (HSCT) is increasingly used as a curative option for adult T-cell leukemia (ATL), an intractable mature T-cell neoplasm causally linked with human T-cell leukemia virus type I (HTLV-I). We compared outcomes of 386 patients with ATL who underwent allogeneic HSCT using different graft sources: 154 received human leukocyte antigen (HLA)-matched related marrow or peripheral blood; 43 received HLA-mismatched related marrow or peripheral blood; 99 received unrelated marrow; 90 received single unit unrelated cord blood. After a median follow-up of 41 months (range, 1.5-102), 3-year overall survival for entire cohort was 33% (95% confidence interval, 28%-38%). Multivariable analysis revealed 4 recipient factors significantly associated with lower survival rates: older age (> 50 years), male sex, status other than complete remission, and use of unrelated cord blood compared with use of HLA-matched related grafts. Treatment-related mortality rate was higher among patients given cord blood transplants; disease-associated mortality was higher among male recipients or those given transplants not in remission. Among patients who received related transplants, donor HTLV-I seropositivity adversely affected disease-associated mortality. In conclusion, allogeneic HSCT using currently available graft source is an effective treatment in selected patients with ATL, although greater effort is warranted to reduce treatment-related mortality.
Jun Okamura, Atae Utsunomiya, Ryuji Tanosaki, Naokuni Uike, Shunro Sonoda, Mari Kannagi, Masao Tomonaga, Mine Harada, Nobuhiro Kimura, Masato Masuda, Fumio Kawano, Yuji Yufu, Hiroyoshi Hattori, Hiroshi Kikuchi, Yoshio Saburi
Allogeneic stem-cell transplantation with reduced conditioning intensity as a novel immunotherapy and antiviral therapy for adult T-cell leukemia/lymphoma.
Blood. 2005 May 15;105(10):4143-5. doi: 10.1182/blood-2004-11-4193. Epub 2005 Jan 21.
Abstract/Text
Sixteen patients with adult T-cell leukemia/lymphoma (ATL) who were all over 50 years of age underwent allogeneic stem cell transplantation with reduced-conditioning intensity (RIST) from HLA-matched sibling donors after a conditioning regimen consisting of fludarabine (180 mg/m2), busulfan (8 mg/kg), and rabbit antithymocyte globulin (5 mg/kg). The observed regimen-related toxicities and nonhematologic toxicities were all found to be acceptable. Disease relapse was the main cause of treatment failure. Three patients who had a relapse subsequently responded to a rapid discontinuation of the immunosuppressive agent and thereafter achieved another remission. After RIST, the human T-cell leukemia virus type 1 (HTLV-1) proviral load became undetectable in 8 patients. RIST is thus considered to be a feasible treatment for ATL. Our data also suggest the presence of a possible graft-versus-ATL effect; an anti-HTLV-1 activity was also found to be associated with this procedure.
Ryuji Tanosaki, Naokuni Uike, Atae Utsunomiya, Yoshio Saburi, Masato Masuda, Masao Tomonaga, Tetsuya Eto, Michihiro Hidaka, Mine Harada, Ilseung Choi, Takeharu Yamanaka, Mari Kannagi, Masao Matsuoka, Jun Okamura
Allogeneic hematopoietic stem cell transplantation using reduced-intensity conditioning for adult T cell leukemia/lymphoma: impact of antithymocyte globulin on clinical outcome.
Biol Blood Marrow Transplant. 2008 Jun;14(6):702-8. doi: 10.1016/j.bbmt.2008.03.010.
Abstract/Text
Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective treatment for adult T cell leukemia/lymphoma (ATLL), but shows high mortality. We evaluated the feasibility of reduced-intensity transplantation using fludarabine and busulfan, with particular focus on the clinical impact of antithymocyte globulin (ATG) in the conditioning regimen. Fourteen elderly patients with aggressive ATLL were enrolled in the current study without ATG, and were compared to those in 15 patients who were treated similarly, but with ATG, in our previous study. Engraftment was prompt, and treatment was tolerable. Overall (OS) and progression-free survival (PFS) at 3 years were 36% and 31%, respectively. HTVL-1 proviral load became undetectable by the polymerase chain reaction in 62% of patients. Compared to the previous study with ATG, complete donor chimera was significantly delayed. Although early relapse tended to be decreased, OS or PFS was not improved significantly. Analysis of combined data from both our current and previous studies disclosed that grade I-II acute GVHD was the only factor that favorably affected OS and PFS. These data suggested the presence of a graft-versus-ATLL effect and the feasibility of a transplant procedure without ATG in elderly ATLL patients, but could not demonstrate the clinical benefit of incorporating ATG.
I Choi, R Tanosaki, N Uike, A Utsunomiya, M Tomonaga, M Harada, T Yamanaka, M Kannagi, J Okamura, ATLL allo-HSCT Study Group
Long-term outcomes after hematopoietic SCT for adult T-cell leukemia/lymphoma: results of prospective trials.
Bone Marrow Transplant. 2011 Jan;46(1):116-8. doi: 10.1038/bmt.2010.92. Epub 2010 Apr 19.
Abstract/Text
We have previously conducted clinical trials of allogeneic hematopoietic SCT with reduced-intensity conditioning regimen (RIC) for adult T-cell leukemia/lymphoma (ATLL)-a disease caused by human T-lymphotropic virus type 1 (HTLV-1) infection and having a dismal prognosis. Long-term follow-up studies of these trials revealed that 10 of the 29 patients have survived for a median of 82 months (range, 54-100 months) after RIC, indicating a possible curability of the disease by RIC. However, we have also observed that the patterns of post-RIC changes in HTLV-1 proviral load over time among the 10 survivors were classified into three patterns. This is the first report to clarify the long-term outcomes after RIC for ATLL patients.
